Comparing the mechanism of four classic Gualou-Xiebai prescriptions for cardiovascular diseases with phlegm and blood stasis syndrome based on molecular network modeling

Background:Four classical Traditional Chinese Medicine prescriptions,namely Gualou Xiebai Baijiu decoction,Gualou Xiebai Banxia decoction(GLXBBX),Zhishi Xiebai Guizhi decoction(ZSXBGZ)and Danlou prescription(DL),have been frequently used for treatment of phlegm and blood stasis syndrome(PBSS)-related cardiovascular diseases.However,its therapeutic mechanism has not been clearly elucidated.This study aimed to explore PBSS and its molecular mechanism,clarify and compare the mechanisms of four prescriptions in treating PBSS-related diseases.Method:In this study,we collected four prescriptions’compounds,predicted therapeutic targets,and enriched pathways which were based on network pharmacology.Then,we analysed the commen and different mechanisms by combing the network of components,targets and pathways.Finally,molecular docking was engaged to assess the binding potential of key compounds and hub targets.Results:We showed that four prescriptions’intersection genes(VEGFA,SRC,EGFR,etc.)were commonly enriched in PI3K-AKT signaling pathway,HIF-1 signaling pathway,etc.In addition,platelet activation and cAMP signaling pathway were singly enriched from the GLXBBX through unique compounds 12,13-epoxy-9-hydroxynonadeca-7,10-dienoic acid and Cyclo(L-tyrosyl-L-phenylalanyl).These bioactive compounds may exert GLXBBX’s unique pharmacological pathways via involving in mediating PPARA,PTGER3,etc.Sphingolipid signaling pathway was singly enriched from the ZSXBGZ through unique compounds tetramethoxyluteolin,ergosterol peroxide,etc.These bioactive compounds could mediate ADORA1,ADORA3 and TNFRSF1A to regulate ZSXBGZ’s unique pharmacological pathways.AMPK signaling pathway was singly enriched from the DL through unique compounds kaempferol,evofolinb,ethyl acid and aureusidin.These bioactive compounds were involved in mediating the main targets of AMPK signaling pathway,such as TNF,TNFRSF1A,etc.Conclusions:Our research demonstrated that GLXB-prescriptions involved in almost all pathological stages of PBSS-related cardiovascular diseases by modulating high-frequency shared pathways and targets mainly through key compounds(quercetin,mandenol,sitosteryl acetate and luteolin,etc.),for example,participate in the process of atherosclerosis,lipid metabolism,inflammation,immune response,thrombosis,inhibit inflammatory factors and platelet aggregation,regulate immune function,vascular function,oxidative stress.In addition to common pharmacological efficacies,there could also be specificities among GLXB prescriptions due to different compounds.For example,GLXBBX tends to regulate the function of vascular and endothelial barrier,prevent thrombosis.ZSXBGZ tends to regulate lipid metabolism and protect the heart from lipid accumulation.DL tends to maintain energy homeostasis and improve inflammation.

Effect of Gualou Xiebai Banxia decoction combined with Danshen Decoction on clinical efficacy of unstable angina with phlegm and blood stasis syndrome

Objective:To observe the clinical efficacy and safety of Gualou Xiebai Banxia decoction combined with Danshen decoction on unstable angina(UA)with phlegm and blood stasis syndrome.Method:Eighty patients with UA were randomly divided into treatment group(40 cases)and control group(40 cases)by random number table.The control group was given conventional western medicine treatment,and the experimental group was given Gualou Xiebai Banxia decoction and Danshen decoction on the basis of the control group.Both groups were treated for 4 weeks.Before and after treatment,the angina attacks,dosage of nitroglycerin,traditional Chinese medicine syndrome score,quality of life score,blood lipid,coagulation index and clinical total efficacy were observed and recorded.Results:After 4 weeks of treatment,the attack times and duration of angina in the two groups were both decreased compared with those before treatment.And the treatment group was more significantly reduced than the control group,the difference was statistically significant(p<0.05);the consumption of nitroglycerin of the treatment group was 90.0%,which was better than 67.5%of the control group,the difference was statistically significant(p<0.05);the total effective rate of the treatment group was 90%,which was better than 65%of the control group,the difference was statistically significant(p<0.05);the traditional Chinese medicine(TCM)syndrome score of the experimental group was lower than that of the control group,the differences was significant(p<0.05).The improvement of low density lipoprotein(LDL-C),total cholesterol(TC)and prothrombin time(PT)in the experimental group was better than that in the control group(p<0.05).During the study,there were no obvious adverse reactions in both groups.Conclusion:Gualou Xiebai Banxia decoction combined with Danshen decoction can effectively relieve the attack of angina and the consumption of nitroglycerin,improve clinical symptoms,regulate blood lipid and blood flow state,and improve the quality of life of patients with UA,with good clinical efficacy and safety.

山楂消脂胶囊对非急性期冠心病患者颈动脉内-中膜厚度和斑块积分的影响

目的观察山楂消脂胶囊对非急性期冠心病痰瘀证患者颈动脉内-中膜厚度（IMT）和斑块积分的影响。方法本研究采用前瞻性研究方法，将符合诊断标准的102例非急性期冠心病痰瘀症患者按随机数字表法分为两组。对照组（50例）给予西药常规治疗；观察组（52例）在对照组基础上加用山楂消脂胶囊（主要成分为山楂、大黄）0.7 g，每日3次，疗程均为6个月。观察两组急性心脑血管事件的发生率，同时比较治疗前后两组患者颈动脉IMT和斑块积分，以及痰浊证和血瘀证积分的变化和不良反应。结果观察组急性心脑血管事件发生率较对照组明显降低（5.77%比20.00%，P＜0.05）；两组治疗后颈动脉IMT、斑块积分及痰浊证积分和血瘀证积分均较本组治疗前明显降低，且以观察组降低更显著〔颈动脉IMT（mm）：0.80±0.13比0.95±0.12，斑块积分（分）：1.35±0.65比1.75±0.88，痰浊证积分（分）：20.98±6.42比35.55±9.22，血瘀证积分（分）：23.23±5.12比28.95±6.38，P＜0.05或P＜0.01〕。观察组有2例出现腹痛，无其他明显不良反应。结论山楂消脂胶囊可能通过祛痰、化瘀作用，减轻颈动脉内中膜的厚度，降低斑块积分，从而稳定斑块，减少急性心脑血管事件的发生。

Study on Correspondence between Prescription and Syndrome and the Essence of Phlegm and Blood Stasis Syndrome in Coronary Heart Disease Based on Metabonomics

Studying the essence of a syndrome has been a key challenge in the field of Chinese medicine.Until now,due to limitations of the methods available,the progress towards understanding such complicated systems has been slow.Metabonomics encompasses the dynamics,composition and analysis of metabolites,enabling the observation of changes in the metabolic network of the human body associated with disease.Being from the point of view of the whole organism,metabonomics provides an opportunity to study the essence of a syndrome to an unprecedented level.Phlegm and blood stasis syndrome is the main syndrome associated with coronary heart disease（CHD）,which bring difficulties in clinical treatment due to difficulties associated with differentiation of symptoms and signs.The fundamental differences of material between the two also need to be interpreted.The authors consider that we can use the method of combining a disease（in this case CHD）with associated syndromes（phlegm and blood stasis syndrome）to select patients with phlegm and blood stasis syndrome of CHD,and utilize metabonomics to explore the essence of the syndrome by difference analysis of metabolite spectra.Meanwhile,we can study the syndrome in CM,observe the change regularity of metabolism spectra after the treatment of corresponding and non-corresponding prescription and syndrome,in order to validate the material fundament in the progress of syndrome formation and their differences.This will not only have great significance in enhancing the ability to identify syndrome of phlegm and blood stasis in CHD and to establish the clinical curative criteria,but will also offer a new approach of studying the essence for a syndrome using metabonomics.

Exploration of Syndrome Differentiation Patterns in Coronary Heart Disease Patients during Peri-Operative Stage of Coronary Artery Bypass Graft

Objective: To explore the patterns of Syndrome Differentiation (SD) of coronary heart disease (CHD) patients in peri-operative stage of coronary artery bypass graft (CABG).Methods: One week after operation, thirty-seven CHD patients, who received CABG of internal mammary artery or great saphena vein under conventional general anesthesia with low or middle temperature extracorporeal circulation were differentiated as various syndromes, with the pre- or post-operational EKG, color Doppler echocardiography were done during and after operation. The hemodynamic parameters were monitored.Results: In the CHD patients, 64.9% were differentiated as Qi-Yin deficiency, 67.6% were complicated with phlegm syndrome and 62.2% with blood stasis, suggesting that Qi-deficiency, phlegm and stasis are the basic pathogenetic factors in patients with CABG. Moreover, the peri-operative syndrome was correlated with the condition of coronary artery lesion, heart and lung functions before operation, and the extracorporeal circulation time during the operation.Conclusion: TCM SD conducting in peri-operative stage might be useful in exploring the patterns of syndrome alteration which provided a basis for preventing peri-operative complications and elevating success rate of operation.